The epipodophyllotoxin class of antitumor agents includes the active compounds VM-26 (NSC-122819) and VP-16-213 (NSC-141540). These compounds have been shown to be very effective against several tumor types. For example, VM-26 has exhibited useful therapeutic benefits against Hodgkin's disease, while VP-16-213 is one of the most active drugs ever tested in the L1210 tumor system. We propose to develop a general approach to the synthesis of these molecules which should permit the production of many structural analogues and derivatives. The synthetic approach to these molecules involves the construction of a key intermediate from three distinct molecular fragments followed by a rearrangement-cyclization process which would produce the pentacyclic skeleton of the aglycones. Studies on this approach, as well as several others, are continuing.